TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance

Cancer Cell. 2005 Nov;8(5):369-80. doi: 10.1016/j.ccr.2005.10.012.


Tumors escape from immune surveillance by producing the immunosuppressive cytokine TGF-beta. However, the mechanism by which TGF-beta inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-beta acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products-namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma-which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-gamma involves binding of TGF-beta-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-beta/Smad pathway. Neutralization of systemic TGF-beta in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-beta suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factors / metabolism
  • Animals
  • Blood Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytotoxicity, Immunologic / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Granzymes
  • Interferon-gamma / metabolism
  • Interleukin-2 / physiology
  • Mice
  • Serine Endopeptidases / metabolism
  • Smad Proteins / metabolism
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Cytotoxic / physiology*
  • Transforming Growth Factor beta / physiology*
  • Tumor Escape*


  • Activating Transcription Factors
  • Blood Proteins
  • Interleukin-2
  • Smad Proteins
  • Transforming Growth Factor beta
  • Interferon-gamma
  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases